Insulin resistance is a key pathogenic component of Type 2 diabetes and is also associated with a variety of other clinical conditions ranging from pregnancy to neurodegenerative disease. Despite significant investigation, the mechanisms underpinning insulin resistance are not fully understood. In particular, there have been few studies looking at epigenetic aspects of insulin resistance, despite the fact that several lines of evidence converge to suggest that epigenetic events figure prominently in the development of this condition. In this proposal, we will generate genome-scale maps of insulin resistant and insulin sensitive human adipocytes. These maps will include DNA methylation patterns and the locations of various modified histones. In particular, we will look at cells made insulin resistant using glucocorticoids and TNF1, and compare these to cells harvested directly from insulin resistant individuals. In this way we hope to identify a core set of epigenomic alterations that mark the insulin resistant state. Motif finding and other computational approaches will allow us to draw inferences about key transcriptional pathways operating in these cells, which we will validate using a variety of genetic, biochemical, and pharmacological means. The proposal overall represents the first systematic examination of the epigenetic basis of human insulin resistance. Public Health Relevance: Insulin resistance is a key component of many clinical disorders, particularly obesity and Type 2 diabetes. Understanding the epigenomic basis of insulin resistance will provide novel insights into the mechanisms by which insulin resistance develops, which in turn will lead to new therapeutic strategies.